title: IKZF1 and CRLF2 gene alterations correlate with poor prognosis in Japanese BCR-ABL1-negative high-risk B-cell precursor acute lymphoblastic leukemia.
abstract: BACKGROUND
  Genome-wide analysis studies have demonstrated that IKZF1, CRLF2, and JAK2 gene alterations correlate with poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the prognostic significance for these gene alterations has not been clarified in Japanese patients.
  
  
  METHODS
  A total of 194 patients with BCP-ALL enrolled in the Japanese Children's Cancer & Leukemia Study Group ALL 2004 clinical trial were assessed for the presence of three different gene alterations: IKZF1 deletions, CRLF2 expression and JAK2 mutation.
  
  
  RESULTS
  IKZF1 deletions and CRLF2-high expression were identified in 22 of 177 (12%) patients and in 15 of 141 (11%) patients, respectively. However, JAK2 R683 mutation was detected only one of 177 patients. The 4-year event-free survival (4y-EFS) was different when comparing patients with or without IKZF1 deletions (68.2% vs. 85.2%; P = 0.04) and was also different when comparing patients with different CRLF2 expression levels (high, 66.7% vs. low, 88.1%; P = 0.03). The differences in 4y-EFS were statistically significant in patients with ALL in the National Cancer Institute (NCI)-high risk group (HR-ALL) (IKZF1 deletions: yes, 58.3% vs. no, 87.0%, P = 0.02; CRLF2 expression: high, 55.6% vs. low, 85.3%, P = 0.04) but not in patients with ALL in the NCI-standard risk group (SR-ALL; IKZF1 deletions: yes, 80.0% vs. no, 84.4%, P = 0.75; CRLF2 expression: high, 83.3% vs. low, 89.2%, P = 0.77). Coexistence of IKZF1 deletions and CRLF2-high expression associated with poor outcomes.
  
  
  CONCLUSIONS
  IKZF1 deletions and CRLF2-high expression predicted poor outcomes in patients with HR-ALL but not in patients with SR-ALL in our Japanese cohort.
authors.affiliation: National Hospital Organization Nagoya Medical Center Clinical Research Center, Nagoya, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamada
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yamaji
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hori
authors.forename: Masahito
authors.initials: M
authors.lastname: Tsurusawa
authors.forename: Arata
authors.initials: A
authors.lastname: Watanabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kikuta
authors.forename: Keiko
authors.initials: K
authors.lastname: Asami
authors.forename: Akiko M
authors.initials: AM
authors.lastname: Saito
authors.forename: Keizo
authors.initials: K
authors.lastname: Horibe
mesh_terms: D044466:Asian People; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl; D015973:Gene Expression Regulation, Leukemic; D055106:Genome-Wide Association Study; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D007564:Japan / Q000453:epidemiology; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D018121:Receptors, Cytokine / Q000096:biosynthesis* / Q000235:genetics; D017384:Sequence Deletion; D015996:Survival Rate
chemical_list: C581634:BCR-ABL1 fusion protein, human; C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; D018121:Receptors, Cytokine; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: CRLF2; IKZF1; JAK2; acute lymphoblastic leukemia